Iron deficiency remains one of the foremost nutrient deficiencies in children in the world. Whereas over 40 studies have described the effects of postnatally acquired dietary iron deficiency on neurodevelopment, less attention has been paid to the immediate and long-term sequelae of fetal and neonatal brain iron deficiency. Fetal/neonatal iron deficiency occurs in three clinical conditions; severe maternal iron deficiency, intrauterine growth retardation (IUGR) and pregnancies complicated by diabetes mellitus. The former complicates 30-50% of pregnancies in the developing world. The latter two account for iron deficiency in 225,000 newborn infants per year in the US. Iron deficiency affects at least three major aspects of early brain development: energy metabolism, monoamine neurotransmitter homeostasis, and myelination. Our laboratory has focused on the former as it relates to the developing hippocampus; the major neural circuit that subserves explicit memory. Nutritional insults (e.g. iron deficiency) that affect early hippocampal development are likely to impair memory function. Our long term objectives are to understand the mechanisms by which late fetal and early postnatal iron deficiency alter the biochemistry, structure, cell signaling, and electrical output of the hippocampus and how this in turn alters hippocampally based memory behavior. Our specific aims are to demonstrate that fetal/neonatal iron deficiency 1) causes abnormalities in recognition memory in human infants of diabetic mothers at birth and following iron repletion at 6, 12, 18 and 24 months as documented by event related potentials and behavioral tasks; and 2) alters hippocampal biochemistry, decreases dendritic arborization, neuronal cell-signaling kinase concentrations and long-term potentiation, and impairs hippocampally dependent trace conditioning in the rat while iron deficient and following iron repletion. In order to understand the specific effect of iron on the hippocampus, we will begin to identify potential transcriptional and post-transcriptional mechanisms by which iron regulates key hippocampal structural and functional proteins identified in specific aim 2.